The decline in kidney function is unrelenting in many patients with chronic kidney disease (CKD) despite current therapies. Animal studies show that a systemic acid load induces kidney generation of pro-fibrotic mediators and kidney injury. Single-center clinical studies have further found that chronic alkali treatment, such as with oral sodium bicarbonate, is renoprotective in people with low, or even normal, serum bicarbonate concentrations. These promising results are underscored by the emphasis of this therapy as a potential clinical trial intervention in a 2011 NIDDK Conference and the specific suggestion by the present RFA. Before a large definitive trial can be undertaken, however, it is important to examine carefully the tolerability, compliance and safety features of various doses of oral bicarbonate. The present application for a pilot study is designed precisely for this purpose. In a two-center, single-blind pilot study, 140 patients with albuminuric stage 3-4 CKD and low-to-normal serum bicarbonate concentrations (20 - 26 meq/L) will be randomly assigned to one of three treatment arms: (i) low- dose oral sodium bicarbonate (0.4 meq/kg lean body weight/day; n = 52), (ii) high-dose oral sodium bicarbonate (0.7 meq/kg lean body weight/day; n = 52), or (iii) placebo for one-year. The major objectives are to assess: (i) the tolerability and compliance of low-dose and high-dose sodium bicarbonate by performing pill counts and measuring changes in urinary net acid excretion (NAE), (ii) the safety profile of low-dose and high- dose sodium bicarbonate using clinical parameters, such as blood pressure, and coronary artery calcium score assessed by computed tomography scan, and (iii) the efficacy of low-dose and high-dose sodium bicarbonate on two kidney-injury biomarkers (albumin and N-acetyl--D-glucosaminidase) in the urine. Built into this parallel design is an initial one-month period to determine the relationship between various bicarbonate doses (0.2 - 0.7 meq/kg lean body weight/day) and urinary NAE in a pragmatic setting. The results from this pilot study will help to design the large, definitive trial by delineating the tolerability, compliance, and safety featuresof two rational doses of chronic oral sodium bicarbonate therapy. While the intermediate efficacy (urinary biomarker) results of this pilot study will also be informative, inconclusive efficacy results will not preclude the planning of a large trial, since positive results using glomerular filtration rate as an outcome have already been demonstrated in previous small trials. Chronic oral sodium bicarbonate is a promising adjunct therapy to slow CKD. If its renoprotective effects can be demonstrated in a large definitive trial, the broad applicability of this inexpensive therap will significantly transform clinical practice and have major public health implications.